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Doctors who carried out a stem cell transplant on an
HIV-infected man with leukaemia in 2007 say they now believe the man to have
been cured of HIV infection as a result of the treatment, which introduced stem
cells which happened to be resistant to HIV infection.

The man received bone marrow from a donor who had natural
resistance to HIV infection; this was due to a genetic profile which led to the
CCR5 co-receptor being absent from his cells. The most common variety of HIV
uses CCR5 as its ‘docking station’, attaching to it in order to enter and
infect CD4 cells, and people with this mutation are almost completely protected
against infection.

The case was first reported at the 2008 Conference on
Retroviruses and Opportunistic Infections in Boston,
and Berlin
doctors subsequently published a detailed case history in the New England Journal of Medicine in
February 2009.

They have now published a follow-up report in the journal Blood,
arguing that based on the results of extensive tests, “It is reasonable to
conclude that cure of HIV infection has been achieved in this patient.”

The case history

The 'Berlin
patient' is an HIV-positive man who developed acute myeloid leukaemia, received
successful treatment and subsequently experienced a relapse in 2007 that
required a transplant of stem cells.

Doctors chose stem cells from an individual who had an
unusual genetic profile: a mutation inherited from both parents that resulted
in CD4 cells that lacked the CCR5 receptor. This mutation, called CCR5 delta 32
homozygosity, is present in less than 1% of Caucasians in northern and western
Europe, and is associated with a reduced risk of becoming infected with HIV.

This is because all new infecting viruses need to use the
CCR5 receptor on CD4 cells when infecting an immune system cell of the CD4
type.

Later in the course of HIV infection another type of virus
emerges that can use the CXCR4 receptor instead.

Before the stem cell transplant the patient received
chemotherapy treatment that destroyed most immune cells and total body
irradiation, and also received immunosuppressive drugs to prevent rejection of
the stem cells.

Antiretroviral therapy was halted on the day of the
transplant, and the patient had to receive a second stem cell transplant 13
days after the first one, due to a further relapse of leukaemia.

The patient continued to receive immunosuppressive treatment
to prevent rejection for 38 months, and at 5, 24 and 29 months post-transplant
colon biopsies were taken to investigate possible graft-versus-host disease in
the intestine. At each investigation additional samples were taken to check for
signs of HIV infection in the abundant immune cells of the gut wall.

During the 38 month follow-up period the donor CD4 cells
repopulated the mucosal immune system of the gut, to such an extent that the
frequency of CD4 cells was almost twice as high as in HIV-negative healthy
controls, and this phenomenon was also seen in a control group of ten
HIV-negative individuals who received stem cell transfers.

The repopulation of CD4 cells was accompanied by the
complete disappearance of host CD4 cells, and after two years the patient had
the CD4 count of a healthy adult of the same age.

One of the challenges for any approach to curing HIV
infection is long-lived immune system cells, which need to be cleared before a
patient can be cured. In the case of the Berlin
patient CCR5-bearing macrophages could not be detected after 38 months, suggesting that
chemotherapy had destroyed these longer-lived cells, and that they had also
been replaced by donor cells.

The German researchers and San Francisco-based immunologist
Professor Jay Levy believe that the findings point to the importance of
suppressing the production of CCR5-bearing cells, either through transplants or
gene therapy.

The patient did not resume antiretroviral therapy after the
transplant.

Nevertheless HIV remained undetectable by both viral load
testing (RNA) and tests for viral DNA within cells, and HIV antibody levels
declined to the point that the patient has no antibody reactivity to HIV core
antibodies, and only very low levels of antibodies to the HIV envelope
proteins.

Seventeen months after the transplant the patient developed
a neurological condition, which required a brain biopsy and lumbar puncture to
sample the cerebrospinal fluid for diagnostic purposes. HIV was also
undetectable in the brain and the CSF.

An additional indication that HIV is not present lies in the
fact that the patient’s CD4 cells are vulnerable to infection with virus that
targets the CXCR4 receptor. If any virus with this preference was still
present, the researchers argue, it would be able to swiftly infect the large
population of memory CD4 cells that has emerged.

The Berlin patient speaks to the press

The `Berlin patient`,
Timothy Ray Brown, a US
citizen who lives in Berlin,
was interviewed this week by German news magazine Stern.

His course of treatment for leukaemia was gruelling and
lengthy. Brown suffered two relapses and underwent two stem cell transplants,
as well as a serious neurological disorder that flared up when he seemed to be
on the road to recovery.

The neurological problem led to temporary blindness and
memory problems. Brown is still undergoing physiotherapy to help restore his
coordination and gait, as well as speech therapy.

Friends have noticed a personality change too: he is much
more blunt, possibly a disinhibition that is related to the neurological
problems.

On being
asked if it would have been better to live with HIV than to have beaten it in
this way he says “Perhaps. Perhaps it would have been better, but I don’t ask
those sorts of questions anymore.”

Timothy
Brown is now considering a move from Berlin to
Barcelona or San Francisco, and, reports Stern magazine, enjoying a drink and a
cigarette.

Stern also interviewed Dr Gero Hütter, who was in charge of Timothy Brown’s treatment. Dr Hütter
told Stern that as a scientist he was
“in the right place, at the right time” and that “for me it is important to
have overthrown the dogma that HIV can never be cured. Something like this is
the greatest thing one can achieve in medical research”.

Implications for future approaches to curing HIV infection

If a cure has been achieved in this patient, it points the
way towards attempts to develop a cure for HIV infection through genetically
engineered stem cells.

The German researchers and San Francisco-based immunologist
Professor Jay Levy believe that the findings point to the importance of
suppressing the production of CCR5-bearing cells, either through transplants or
gene therapy.

Scientists were sufficiently intrigued by the Berlin patient
that they met in Berlin in 2009 to discuss how they could coordinate efforts to
identify CCR5-delta32 homozygous donors and expand the supply of stem cells
from these donors, for example through sampling blood cells from the umbilical
cord of babies born to mothers who are homozygous for CCR5-delta32, in order to
eventually facilitate stem-cell therapy.

Gene therapy techniques which can transform stem cells – and
all their descendents – into cells resistant to HIV entry may be a more
practical option than looking for matching donors.

Several US
research groups announced in October 2009 that they had received funding to
explore techniques for engineering and introducing CCR5-deficient stem cells.

If these approaches prove successful they will be expensive,
so in the early stages it is likely that they would be reserved for people with
no remaining treatment options or a cancer requiring bone marrow or stem cell
transfer.

As Timothy Brown’s experience shows, curing HIV infection
through ablative chemotherapy, immunosuppressive drugs and stem cell transfer
is not a course of treatment for the faint-hearted. It has required courage,
determination and a lot of support to become the first person to be pronounced
`cured` of HIV infection.

NAM’s information is intended to support, rather than replace, consultation with a healthcare professional. Talk to your doctor or another member of your healthcare team for advice tailored to your situation.